Polymers are of great interest that are soluble both in organic solvents and in water (i.e., amphiphilic polymers) and that are suitably activated at the termini to obtain ready linkage to compounds with biological activity. Amphiphilic polymer derivatives have been proposed for modification of the physical, chemical, and pharmacological properties of biologically active materials and surfaces for biomaterials.
For example, surface modification of enzymes and polypeptides as potential therapeutic drugs is proposed by A. Abuchoswki and F. F. Davis, in "Enzymes as Drugs", J. S. Holcenbery and J. Roberts ed., Wiley & Sons, p. 367-384 (1981). It is known that polymer derivatized proteins have increased circulation life in the body, decreased immunogenic reaction, and allow some targeting.
Amphiphilic polymers have been proposed for the preparation of prodrugs as illustrated by P. Ferruti and E. Ranucci in "High Performance Biomaterials", M. Szycher Ed., Technomics Pub. Inc., p. 539-572 (1991); and by P. Caliceti, C. Monfardini, L. Sartore, O. Schiavon, F. Baccichetti, F. Carlassare and F. M. Veronese, in "Preparation and Properties of Monomethoxypoly (ethylene glycol)-Doxorubicine Conjugates Linked by an Amino Acid or Peptide as Spacer", 11 Farmaco, 48, 919-932 (1993).
Biocompatible polymers have been proposed for modifying surfaces as shown in E. W. Merrill, in "Poly(ethylene oxide) and Blood Contact: A Chronicle of One Laboratory; in Poly(ethylene glycol) Chemistry: Biotechnical and Biomedical Applications," J. M. Harris ed., p. 199-220 (1992), Plenum Publishing Corporation, New York; C. G. Golander; and by J. N. Herron, K. Lim, P. Stenius and J. D. Andrade in "Properties of Immobilized PEG Films and Interaction with Protein: Experiments and Modelling," p. 221-245 (1992) ibidem.
Bioseparation by two phase partioning has been proposed with amphiphilic polymers as shown by D. E. Brooks, J. M. Van Alstine, K. A. Sharp and S. J. Stocks, in "PEG-Derivatized Ligands with Hydrophobic and Immunological Specificity: Applications in Cell Separation," p. 57-71 (1992) ibidem; and by G. Johansson in "Affinity Partioning in PEG-Containing Two-Phase Systems," p. 73-84 (1992) ibidem.
Liposomes have been proposed for modification with amphiphilic polymers as shown by D. Papahadjopoulos, T. M. Allen, A. Gabizon, E. Mayhew, K. Matthay, S. K. Huang, K. D. Lee, M. C. Woodle, D. D. Lasic, C. Redemann and F. J. Martin in "Sterically Stablished Liposomes: Improvements in Pharmacokinetics and Antitumor Therapeutic Efficacy," Pro. Natl. Acad. Sci. 88, 11460-11464 (1991).
Amphiphilic polymers have been proposed for liquid phase synthesis of oligomeric peptides and nucleotides as shown by G. M. Bonora, G. Biancotto, M. Maffini, C. L. Scremin in "Large Scale, Liquid Phase Synthesis of Oligonucleotides by the Phosphoramidite Approach," Nucleic Acids Research, 21, 1213-1217 (1993).
Colloidal particles have been proposed for coating with a hydrophilic coating of an amphiphilic polymer for controlled delivery as illustrated in L. Illum, I. M. Hunneyball, and S. S. Davis, Inter. J. Pharm., 29, 53-65 (1986).
Enzymes have been proposed for modification with amphiphilic polymers for biocatalysis in organic solvents as shown by Y. Inada, K. Takahashi, T. Yoshimoto, A. Ajima, A. Matsushima and Y. Saito in "Application of Poly(ethyleneglycol)-Modified Enzymes in Biotechnological Processes: Organic Solvent-Soluble Enzymes", Tibtech, 4, 190-194 (1986).
Several polymers have been studied in connection with the above uses of amphiphilic polymers. Among these polymers are the following: dextran, polyalanine, polyacrylic and polymaleic polymers, poly(ethylene glycol) of various molecular weights, and others. Poly(ethylene glycol) ("PEG") has received the most interest because of its absence of toxicity, antigenicity, immunogenicity, for its degree of amphiphilicity. PEG can be activated at each terminus to be bifunctional. PEG can also be modified to have a reactive moiety at one end. This reactive moiety can be activated for attachment of the monofunctional PEG to biomaterials. Monofunctional PEG avoids, at least in the case of polypeptides, multiple binding with cross linking and aggregation.
Amphiphilic polymers different from PEG have been functionalized and conjugated with proteins. For example, copolymers of acrylic acid with N-acryloylmorpholine ("AcM") have been prepared and the reactive sites activated by conversion to the N-hydroxysuccinimide active ester. These copolymers have multiple active sites and are polyfunctional. The polyfunctional copolymers have been attached to proteins as illustrated by F. M. Veronese, R. Largajolli, C. Visco, P. Ferruti and A. Minucci, J. in Appl. Biochem. Biotechnol. 11, 269-277 (1985). The copolymer modified proteins are soluble in water and many organic solvents and have been shown to be nontoxic by P. Ferruti and E. Ranucci in "High Performance Biomaterials" in M. Szycher ed., Technomics, p. 539-572 (1991). However, the copolymers have the disadvantage of being activated along the chain, which can lead to problems such as aggregation, cross linking and complex mixtures.